A Textbook of Clinical Pharmacology and Therapeutics

382 CANCER CHEMOTHERAPY

MULTI-TARGETED TKIs

Sorafenibandsunitinibare used in the USA as single oral
agents to treat advanced renal cell carcinoma.
Sorafenibincreases median survival by approximately 12
months in patients with advanced refractory renal cell cancer.
It is a small molecule ATP mimetic and competitive inhibitor
of Raf kinase, the VEGF receptor tyrosine kinase and the
platelet-derived growth factor receptor (PDGFR) tyrosine
kinase. It undergoes hepatic oxidation mediated by CYP3A
and glucuronidation (UGT1A1). Adverse effects include skin
rash, hand–foot skin reactions, diarrhoea, hypertension and
bleeding.
Sunitinibdoubled the survival time of imatinib-resistant
GIST tumours and improved survival in advanced renal cell
cancer. It is a small molecule ATP mimetic and competitive
inhibitor of signalling through multiple tyrosine receptor
kinases, including platelet-derived growth factor receptor and
vascular endothelial growth factor receptor. These kinases are
important in angiogenesis. It is metabolized by CYP3A.
Adverse effects include diarrhoea, hypertension, skin discol-
oration, mucositis, fatigue and hypothyroidism. Less fre-
quently, neutropenia, thrombocytopenia and decreases in left
ventricular ejection fraction have been noted.

PROTEASOME INHIBITORS

Bortezomibis the first member of this class. It is effective in
treating refractory multiple myeloma. It is a reversible competi-
tive inhibitor of the proteolytic function of the chymotrypsin-
like activity of the 20S core subunit of the proteasome. The
proteasome can be considered the cellular ‘garbage can’ for
proteins. Proteins once ubiquitinated are destined to be
degraded by the proteasome and exit the proteasome as small
peptides. Proteasome inhibition affects a number of cellular
functions, but a major effect is to disable IκB degradation. IκB
binds to NF-κB and prevents this transcription factor moving
to the nucleus, silencing NF-κB-mediated gene transcription.
Additonally, proteasome inhibition disrupts the homeostasis
of key regulatory proteins (p21, p27 and p53) involved in cell
cycle progression and proliferation. Bortezomibis adminis-
tered intravenously. It undergoes hepatic metabolism via
CYP3A and CYP2D6. Adverse effects include thrombocyto-
penia, fatigue, peripheral neuropathy, neutropenia, gastro-
intestinal disturbances.

HISTONE DEACETYLASE INHIBITORS

Vorinostat(suberoylanilide hydroxamic acid, SAHA) is effect-
ive against refractory cutaneous T-cell lymphoma, producing
a 30% response rate with a median response of 168 days.
Many tumour cells overexpress histone deacetylase enzymes
which deacetylate histones. Vorinostatinhibits these enzymes,
blocking the transcription of genes involved in cell cycle pro-
gression. Vorinostat is administered orally. It undergoes
hepatic glucuronidation and oxidation. Adverse effectsinclude

gastro-intestinal disturbances, fatigue, hyperglycaemia, hyper-

lipidaemia, bone marrow suppression (anaemia, thrombocyto-

penia and neutropenia) and pulmonary embolism.

ANTI-BCL-2 OLIGONUCLEOTIDE

Oblimersenis under review by the FDA as an ‘orphan drug’

for chronic lymphocytic leukaemia. It is an oligonucleotide

that binds mRNA for the anti-apoptotic protein Bcl-2 and

causes it to be degraded, thus promoting apoptosis in cells

overexpressing Bcl-2.

MONOCLONAL ANTIBODIES

Cancer cells express a range of proteins that are suitable tar-

gets for monoclonal antibodies. The development of mono-

clonal antibodies against specific antigens (targets) has been

facilitated by advances in hybridoma technology (i.e. immu-

nizing mice with human tumour cells and screening the

hybridomas for antibodies of interest). Because murine anti-

mouse antibodies have a short half-life and induce human

anti-mouse antibody immune response, they are usually

chimerized or humanized for therapeutic use (Chapter 16).

The nomenclature for therapeutic monoclonal antibodies is to

have the suffix ‘-ximab’ for chimeric antibodies and ‘-umab’

for humanized antibodies. Trastuzumab, one of the first

agents demonstrated to have clinical benefit in cancer therapy,

is discussed below. Other monoclonal antibodies that are used

therapeutically in cancer are detailed in Table 48.10. All are

administered intravenously.

Figure 48.9 shows an example of the 3D structure of a mon-

oclonal antibody.

TRASTUZUMAB

Uses

Trastuzumabis a humanized monoclonal antibody (molecular

weight approximately 100 kDa) that is used as a single agent or

in combinations (e.g. with paclitaxel) to treat metastatic breast

cancer that over-expresses the target-HER2/neu (Erb-2, i.e.

EGFR-1) – about 30% of such cancers do this.

Mechanism of action

This monoclonal antibody binds tightly to the Her-2/Neu

(Erb-B2) glycoprotein, a member of the epidermal growth fac-

tor family of cellular receptors (EGFR). EGFR encodes its own

tyrosine kinase which, upon receptor–ligand binding, nor-

mally autophosphorylates the receptor causing downstream

signalling which increases proliferation, metastatic potential

and evasion of apoptosis. Trastuzumabbinding inhibits such

downstream signalling of the EGFR receptor.

Adverse effects

These include the following:

• infusion reactions involving fever, chills, nausea,
  dyspnoea, rashes;